Maternal natural killer cells at the intersection between reproduction and mucosal immunity

Abstract: Many maternal immune cells populate the decidua, which is the mucosal lining of the uterus transformed during pregnancy. Here, abundant natural killer (NK) cells and macrophages help the uterine vasculature adapt to fetal demands for gas and nutrients, thereby supporting fetal growth. Fetal trophoblast cells budding off the forming placenta and invading deep into maternal tissues come into contact with these and other immune cells. Besides their homeostatic functions, decidual NK cells can respond to pathogens during infection, but in doing so, they may become conflicted between destroying the invader and sustaining fetoplacental growth. We review how maternal NK cells balance their double duty both in the local microenvironment of the uterus and systemically, during toxoplasmosis, influenza, cytomegalovirus, malaria and other infections that threat pregnancy. We also discuss recent developments in the understanding of NK-cell responses to SARS-Cov-2 infection and the possible dangers of COVID-19 during pregnancy

Myocardial Ischemia and Reperfusion Leads to Transient CD8 Immune Deficiency and Accelerated Immunosenescence in CMV-Seropositive Patients

Rationale: There is mounting evidence of a higher incidence of coronary heart disease (CHD) in cytomegalovirus (CMV) seropositive individuals. Objective: The aim of this study was to investigate whether acute MI triggers an inflammatory T-cell response that might lead to accelerated immunosenescence in CMV-seropositive patients. Methods and Results: Thirty-four patients with acute MI undergoing primary PCI (PPCI) were longitudinally studied within 3 months following reperfusion (Cohort A). In addition, 54 patients with acute and chronic MI were analyzed in a cross-sectional study (Cohort B). CMV-seropositive patients demonstrated a greater fall in the concentration of terminally differentiated CD8 effector memory T cells (TEMRA) in peripheral blood during the first 30 min of reperfusion compared with CMV-seronegative patients (-192 vs. -63 cells/µl; p=0.008), correlating with the expression of programmed cell death-1 (PD-1) before PPCI (r=0.8; p=0.0002). A significant proportion of TEMRA cells remained depleted for at least 3 months in CMV-seropositive patients. Using high-throughput 13-parameter flow cytometry and HLA class I CMV-specific dextramers, we confirmed an acute and persistent depletion of terminally differentiated TEMRA and CMV-specific CD8+ cells in CMV-seropositive patients. Long-term reconstitution of the TEMRA pool in chronic CMV-seropositive post-MI patients was associated with signs of terminal differentiation including an increase in KLRG1 and shorter telomere length in CD8+ T cells (2225 bp vs. 3397 bp; p<0.001). Conclusions: Myocardial ischemia and reperfusion in CMV-seropositive patients undergoing PPCI leads to acute loss of antigen-specific, terminally differentiated CD8 T-cells, possibly through PD-1-dependent programmed cell death. Our results suggest that acute MI and reperfusion accelerate immunosenescence in CMV-seropositive patients

CMV-independent increase in CD27−CD28+ CD8+ EMRA T cells is inversely related to mortality in octogenarians

Funder: The author is supported by the British Heart FoundationFunder: British Heart Foundation PG/15/85/31744 and PG/18/25/33587, Newcastle Healthcare Charity, Medical Research Council (G0500997 to TK, CJ and TvZ, G0601333 to TvZ) and the NIHR Biomedical Research Centre in Ageing and Chronic Disease.Funder: BK holds a British Heart Foundation personal chair.Abstract: Cytomegalovirus (CMV) seropositivity in adults has been linked to increased cardiovascular disease burden. Phenotypically, CMV infection leads to an inflated CD8 T-lymphocyte compartment. We employed a 8-colour flow cytometric protocol to analyse circulating T cells in 597 octogenarians from the same birth cohort together with NT-proBNP measurements and followed all participants over 7 years. We found that, independent of CMV serostatus, a high number of CD27−CD28+ CD8 EMRA T-lymphocytes (TEMRA) protected from all-cause death after adjusting for known risk factors, such as heart failure, frailty or cancer (Hazard ratio 0.66 for highest vs lowest tertile; confidence interval 0.51–0.86). In addition, CD27−CD28+ CD8 EMRA T-lymphocytes protected from both, non-cardiovascular (hazard ratio 0.59) and cardiovascular death (hazard ratio 0.65). In aged mice treated with the senolytic navitoclax, in which we have previously shown a rejuvenated cardiac phenotype, CD8 effector memory cells are decreased, further indicating that alterations in T cell subpopulations are associated with cardiovascular ageing. Future studies are required to show whether targeting immunosenescence will lead to enhanced life- or healthspan

Search for dark matter produced in association with bottom or top quarks in √s = 13 TeV pp collisions with the ATLAS detector

A search for weakly interacting massive particle dark matter produced in association with bottom or top quarks is presented. Final states containing third-generation quarks and miss- ing transverse momentum are considered. The analysis uses 36.1 fb−1 of proton–proton collision data recorded by the ATLAS experiment at √s = 13 TeV in 2015 and 2016. No significant excess of events above the estimated backgrounds is observed. The results are in- terpreted in the framework of simplified models of spin-0 dark-matter mediators. For colour- neutral spin-0 mediators produced in association with top quarks and decaying into a pair of dark-matter particles, mediator masses below 50 GeV are excluded assuming a dark-matter candidate mass of 1 GeV and unitary couplings. For scalar and pseudoscalar mediators produced in association with bottom quarks, the search sets limits on the production cross- section of 300 times the predicted rate for mediators with masses between 10 and 50 GeV and assuming a dark-matter mass of 1 GeV and unitary coupling. Constraints on colour- charged scalar simplified models are also presented. Assuming a dark-matter particle mass of 35 GeV, mediator particles with mass below 1.1 TeV are excluded for couplings yielding a dark-matter relic density consistent with measurements

FROM THE HISTORY OF POSOLSKY PRIKAZ: «MEMO» ABOUT THE MYTH

The problem of presentation of authorities was the urgent problem of the political space in Russia in the XVIth century. Posolskiy prikaz played an important role in this process. Forms of presentation of the tzar's authorities and ideological justification of its status and legitimacy were developed in this agency. "The theory of power" in this period was based on well-known historical works verifying the antiquity and might of Russian dynasty of rulers. The aim of this work is the introduction of the new historical source into the scientific sphere as well as its analysis and assessment

The brain is not mental! coupling neuronal and immune cellular processing in human organisms

Significant efforts have been made in the past decades to understand how mental and cognitive processes are underpinned by neural mechanisms in the brain. This paper argues that a promising way forward in understanding the nature of human cognition is to zoom out from the prevailing picture focusing on its neural basis. It considers instead how neurons work in tandem with other type of cells (e.g., immune) to subserve biological self-organization and adaptive behavior of the human organism as a whole. We focus specifically on the immune cellular processing as key actor in complementing neuronal processing in achieving successful self-organization and adaptation of the human body in an ever-changing environment. We overview theoretical work and empirical evidence on “basal cognition” challenging the idea that only the neuronal cells in the brain have the exclusive ability to “learn” or “cognize.” The focus on cellular rather than neural, brain processing underscores the idea that flexible responses to fluctuations in the environment require a carefully crafted orchestration of multiple cellular and bodily systems at multiple organizational levels of the biological organism. Hence cognition can be seen as a multiscale web of dynamic information processing distributed across a vast array of complex cellular (e.g., neuronal, immune, and others) and network systems, operating across the entire body, and not just in the brain. Ultimately, this paper builds up toward the radical claim that cognition should not be confined to one system alone, namely, the neural system in the brain, no matter how sophisticated the latter notoriously is

Enhanced Efficacy of Vaccination With Vaccinia Virus in Old vs. Young Mice.

Immunosenescence is believed to be responsible for poor vaccine efficacy in the elderly. To overcome this difficulty, research into vaccination strategies and the mechanisms of immune responses to vaccination is required. By analyzing the innate and adaptive immune responses to vaccination with vaccinia virus (VACV) in mice of different age groups, we found that immune cell recruitment, production of cytokines/chemokines and control of viral replication at the site of intradermal vaccination were preserved in aged mice and were comparable with younger groups. Analysis of cervical draining lymph nodes (dLN) collected after vaccination showed that numbers of germinal center B cells and follicular T helper cells were similar across different age groups. The number of VACV-specific CD8 T cells in the spleen and the levels of serum neutralizing antibodies 1 month after vaccination were also comparable across all age groups. However, following intranasal challenge of vaccinated mice, body weight loss was lower and virus was cleared more rapidly in aged mice than in younger animals. In conclusion, vaccination with VACV can induce an effective immune response and stronger protection in elderly animals. Thus, the development of recombinant VACV-based vaccines against different infectious diseases should be considered as a strategy for improving vaccine immunogenicity and efficacy in the elderly

Effect of CMV-seropositivity on acute outcome of acute myocardial infarction

CMV-seropositive individuals are more susceptible to coronary heart disease and death from myocardial infarction (MI). To study the potential effects of CMV-seropositivity on the acute course of MI, we monitored 29 CMV-seropositive and 23 CMV-seronegative patients with acute MI. Blood samples were taken in the first 24 h and 3 months after MI. Absolute counts of lymphocyte subpopulations (FACS), immune response to specific and nonspecific antigens (ELISPOT), 31 cytokines in serum (MSD Multi-SpotAssaySystem) and levels of CMVIgG, cardiolipin-IgG and anti-endothelial cell antibodies (ELISA) were assessed. Results: CMV-seropositive patients had increased absolute counts of CD27-negative effector memory and TEMRA T-cells as well as NK cells compared with CMV-seronegative patients (P < 0.05). CMV-seropositive individuals had a lower level of EBV-specific immune response and a higher PHA-nonspecific response (P < 0.05). CMV-seropositive and seronegative patients only varied in serum levels of IL-16 (173 � 83 pg/ml versus 243 � 71 pg/ml respectively; P = 0.029) and IP-10 (275 � 107/ml versus 175 � 87 pg/ml respectively; P = 0.009) in the acute stage of MI. There were no differences in clinical parameters and cardiac MRI results between the two groups. Results showed higher serum levels for IL-17A, IP-10 and IL-10 as well as responses to EBV and PHA for CMV-seropositive individuals (P < 0.05) at 3 months. No rise in titres for CMV-IgG, no new appearances of cardiolipin-IgG and anti-endothelial cell antibodies were noticed at 3 months compared with the acute stage for either group. Conclusion: According to our results CMV-seropositivity does not influence the severity and immediate outcome of acute MI. Acute MI itself does not promote acceleration of autoimmunity

Effect of CMV-seropositivity on acute outcome of acute myocardial infarction

CMV-seropositive individuals are more susceptible to coronary heart disease and death from myocardial infarction (MI). To study the potential effects of CMV-seropositivity on the acute course of MI, we monitored 29 CMV-seropositive and 23 CMV-seronegative patients with acute MI. Blood samples were taken in the first 24 h and 3 months after MI. Absolute counts of lymphocyte subpopulations (FACS), immune response to specific and nonspecific antigens (ELISPOT), 31 cytokines in serum (MSD Multi-SpotAssaySystem) and levels of CMVIgG, cardiolipin-IgG and anti-endothelial cell antibodies (ELISA) were assessed. Results: CMV-seropositive patients had increased absolute counts of CD27-negative effector memory and TEMRA T-cells as well as NK cells compared with CMV-seronegative patients (P < 0.05). CMV-seropositive individuals had a lower level of EBV-specific immune response and a higher PHA-nonspecific response (P < 0.05). CMV-seropositive and seronegative patients only varied in serum levels of IL-16 (173 � 83 pg/ml versus 243 � 71 pg/ml respectively; P = 0.029) and IP-10 (275 � 107/ml versus 175 � 87 pg/ml respectively; P = 0.009) in the acute stage of MI. There were no differences in clinical parameters and cardiac MRI results between the two groups. Results showed higher serum levels for IL-17A, IP-10 and IL-10 as well as responses to EBV and PHA for CMV-seropositive individuals (P < 0.05) at 3 months. No rise in titres for CMV-IgG, no new appearances of cardiolipin-IgG and anti-endothelial cell antibodies were noticed at 3 months compared with the acute stage for either group. Conclusion: According to our results CMV-seropositivity does not influence the severity and immediate outcome of acute MI. Acute MI itself does not promote acceleration of autoimmunity

Arginine Vasopressin Plays a Role in Microvascular Dysfunction After ST‐Elevation Myocardial Infarction

Background Coronary microvascular dysfunction (CMD) predicts mortality after ST‐elevation–myocardial infarction (STEMI). Arginine vasopressin (AVP) may be implicated, but data in humans are lacking, and no study has investigated the link between arginine vasopressin and invasive measures of CMD. Methods and Results We invasively assessed CMD in 55 patients with STEMI treated with primary percutaneous coronary intervention (PPCI), by measuring the index of microcirculatory resistance after PPCI. In a separate group of 45 patients with STEMI/PPCI, recruited for a clinical trial, we measured infarct size and microvascular obstruction with cardiac magnetic resonance (CMR) imaging at 1 week and 12 weeks post‐STEMI. Serum copeptin was measured at 4 time points before and after PPCI in all patients with STEMI. Plasma copeptin levels fell from 92.5 pmol/L before reperfusion to 6.4 pmol/L at 24 hours. Copeptin inversely correlated with diastolic, but not systolic, blood pressure (r=−0.431, P=0.001), suggesting it is released in response to myocardial ischemia. Persistently raised copeptin at 24 hours was correlated with higher index of microcirculatory resistance (r=0.372, P=0.011). Patients with microvascular obstruction on early CMR imaging showed a trend toward higher admission copeptin, which was not statistically significant. Copeptin levels were not associated with infarct size on either early or late CMR. Conclusions Patients with CMD after STEMI have persistently elevated copeptin at 24 hours, suggesting arginine vasopressin may contribute to microvascular dysfunction. Arginine vasopressin receptor antagonists may represent a novel therapeutic option in patients with STEMI and CMD